Fatty acid synthesis underlies two important facets of Trypanosoma brucei pathogenesis: immune evasion and host adaptation. Yet little is known about how these pathways are regulated. This dearth of knowledge is a problem. Without a clear understanding of pathogenesis, the development of new life-saving treatments is limited. The long-term goal is the elucidation of T. brucei pathogenesis to enable the identification of novel drug targets that disrupt host adaptation and immune evasion. The objective of this application is to determine the mechanisms regulating the Elongase (ELO) fatty acid synthesis pathway in T. brucei. The central hypothesis is that ELO fatty acid synthesis is regulated in response to the environment at the first committed step of fatty acid synthesis: the formation of malonyl-CoA by Acetyl-CoA Carboxylase (ACC). The rationale is that once the regulation of ELO fatty acid synthesis and its roles in pathogenesis are defined, it will be possible to pursue new potential targets for chemotherapy. The team is well-positioned to undertake this research with special expertise in this area, strong preliminary data, access to unique reagents, and a research environment with substantial core facilities and robust institutional support for student research. The central hypothesis will be tested with two Specific Aims: (1) Identify the proximate mechanism regulating ELO fatty acid synthesis pathway;and (2) Determine how the environmental lipid supply affects the activity of ACC. The general approach is to modulate ACC activity or environmental fatty acids and assess the effect these changes have upon ACC and ELO activity and parasite environmental adaptation. The proposed work is innovative because it constitutes a novel approach to elucidate T. brucei pathogenesis through study of the environmental regulation of fatty acid synthesis. Once the proposed research is accomplished, it will have contributed new knowledge about the environmental regulation of fatty acid synthesis in T. brucei and enhanced understanding of T. brucei pathogenesis mechanisms. The proposed work will have a positive benefit to human health, because it will constitute the critical first step in mapping the modes of regulation operating upon T. brucei fatty acid synthesis. This accomplishment will be significant because this information will focus efforts on the best drug targets with the greatest potential to destroy the parasite's ability to adapt to the host environment and evade the immune system. PUBLIC HEALTH RELEVANCE: New drugs for Human African Trypanosomiasis (HAT) are desperately needed, but an incomplete understanding of this disease's pathogenesis limits development of new treatment strategies. The proposed work will benefit human health by providing critical understanding of key pathogenic mechanisms in HAT and a means to identify and validate the best drug targets for development of new life-saving treatments. This research will open doors to treating other parasitic diseases, will shed light on pathological processes common to other infectious diseases, and will broaden our general understanding of how cells adapt to their dynamic and often hostile environment.